With current therapy multiple myeloma (MM) is an incurable disease with approximately 16,000 new cases per year in the USA. New approaches and new tumor targeting modalities for therapy are urgently required. In this proposal we will evaluate the tolerability, efficacy, biodistribution and tumor targeting of a novel oncolytic virus delivery system in patients with relapsed or refractory MM. MV-NIS is a recombinant measles virus capable of concentrating radioactive iodine using the thyroid sodium iodide symporter. This grant builds upon years of pre-clinical work by Dr. Russell and his colleagues. This work is now culminating in a therapeutic trial, which is the focus of this grant application. The specific aims of this project follow: Aim 1. Evaluate the safety and maximum tolerated dose level of MV-NIS administered intravenously with and without cyclophosphamide to patients with advanced multiple myeloma and obtain preliminary data on clinical outcome in the context of a Phase I clinical trial. Hypothesis: MV-NIS administered with and without cyclophosphamide to patients with advanced multiple myeloma will safely and selectively target &propagate in myeloma deposits throughout the body leading to tumor cell killing and reduction of tumor burden. Aim 2: To characterize MV-NIS gene expression using 123-I, gamma camera imaging, and SPECT/CT imaging and to determine whether it correlates with disease distribution and/or disease response. Hypothesis: We predict that our ability to track MV-NIS using 123-I will be dependent on the pattern and extent of a patient's disease. One would anticipate that patients with high tumor burden disease and/or focal lesions would be most easily imaged and would have the best hematologic responses. Aim 3: To characterize the time course of expression, replication, biodistribution, and shedding of MV-NIS and to correlate these parameters with CD46 receptor expression in myeloma cells, dose level, and toxicity. Hypothesis: There will be self-limited expression, replication, and shedding of MV-NIS, which will correlate with both CD46 receptor status in myeloma cells and dose level and will be influenced by cyclophosphamide Aim 4: To determine humoral and cellular immune response to the injected virus in the peripheral blood and correlate it with toxicity, viremia, MV-NIS expression and response. Hypothesis: There will be an inverse correlation between early immune response and viral persistence. This unique strategy using MV-NIS (a genetically modified measles virus) to treat patients with relapsed, refractory myeloma has the potential to change the way cancer is treated. MV-NIS, given by vein, should kill myeloma cells. Using simple scans, we should be able to track where MV-NIS goes in the body.